Genetic and Clinical Analysis of ABCA 4 ‐Associated Disease in African American Patients

Abstract

Autosomal recessive Stargardt disease (STGD1) is caused by hundreds of mutations in the ABCA4 gene, which are often specific to racial and ethnic groups. Here, we investigated the ABCA4 variation and their phenotypic expression in a cohort of 44 patients of African American descent, a previously under-characterized racial group. Patients were screened for mutations in ABCA4 by next-generation sequencing and array-comparative genomic hybridization (aCGH), followed by analyses for pathogenicity by in silico programs. Thorough ophthalmic examination was performed on all patients. At least two (expected) disease-causing alleles in the ABCA4 gene were identified in 27 (61.4%) patients, one allele in 11 (25%) patients, and no ABCA4 mutations were found in six (13.6%) patients. Altogether, 39 different disease-causing ABCA4 variants, including seven new, were identified on 65 (74%) chromosomes, most of which were unique for this racial group. The most frequent ABCA4 mutation in this cohort was c.6320G>A (p.(R2107H)), representing 19.3% of all disease-associated alleles. No large copy number variants were identified in any patient. Most patients reported later onset of symptoms. In summary, the ABCA4 mutation spectrum in patients of West African descent differs significantly from that in patients of European descent, resulting in a later onset and “milder” disease.

The intronic ABCA4 c.5461‐10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level

“…Molecular diagnostics of patients with several forms of eye diseases, like STGD, is important to ensure correct diagnosis. The c.5461-10T>C variant investigated in this study has until recently been classified as a variant of unknown effect (Zernant et al 2014;Sangermano et al 2016). Different in silico splice site programmes do not point to the c.5461-10T>C variant as a splice site variant.…”

“…The c.5461‐10T>C variant investigated in this study has until recently been classified as a variant of unknown effect (Zernant et al. ; Sangermano et al. ).…”

Stargardt disease-associated mutation spectrum of a Russian Federation cohort

“…The identified variant Arg2107Cys (rs61750648) was previously reported in African STGD1 patients (September et al 2004;Zernant et al 2014). Therefore, this Russian patient shares variant from African STGD1 population.…”

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…She also had retinitis pigmentosa, which could potentially be explained by a homozygous mutation (Chr1: 94473807 C>T [hg19]; c.G5882A, p.G1961E) in ABCA4 (NM_000350), the most frequently observed disease-associated mutation (~11%) of European ancestry ( Figure 3B and ref. 29).…”